Psychostimulant abuse and addiction is a crushing public health problem. Our laboratories have begun to decipher the functional effects of glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) stimulation on dopamine uptake, clearance, and trafficking of presynaptic dopamine transporters. GLP-1 is an incretin hormone and neuropeptide that is released in response to food intake. GLP-1 acts through both peripheral and central mechanisms to regulate energy homeostasis and the hedonic components of food intake. We and others have hypothesized that peptides that modulate feeding behavior may also regulate brain circuitry responsible for drug reward. In fact, we recently discovered that systemic administration of the GLP-1 long-lasting analogue exendin-4, which is already used clinically in the treatment of type 2 diabetes, reduces the rewarding effects of cocaine in mice. Within the brain, GLP-1Rs are expressed within the hypothalamus, ventral tegmental area, and nucleus accumbens, but are especially enriched in the lateral septum (LS). The LS is (re)emerging as a crucial brain region involved in the hedonic properties of psychostimulants. In the current application, we will first define cellular heterogeneity in GLP-1 receptor expression patterns within the LS and test the hypothesis that GLP-1Rs modulate dopamine neurotransmission and signaling within the LS (Aim 1). These studies will use modern molecular neuroanatomical, biochemical and electrochemical methods. Next, we will test the hypothesis that local GLP-1 receptor signaling within the LS mediates the therapeutic effects of systemic exendin-4 on cocaine reward (Aim 2). We will also examine cocaine- and GLP-1 receptor agonist-induced changes in cellular activation. Our studies will use both pharmacological and genetic approaches, taking advantage of a recently created GLP-1R conditional knockout mouse. These multidisciplinary studies will provide essential foundational knowledge of the role of the GLP-1 receptor in psychostimulant abuse. The commercial availability of several FDA-approved GLP-1 agonists for the treatment of diabetes offers readily translational opportunities to improve human outcomes in psychostimulant abuse.